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Article: Temozolomide, Procarbazine and Nitrosoureas in the Therapy of Malignant Gliomas: Update of Mechanisms, Drug Resistance and Therapeutic Implications.

Kaina, Bernd

2023 Volume 12, Issue 23

Abstract: The genotoxic methylating agents temozolomide (TMZ) and procarbazine and the chloroethylating nitrosourea lomustine (CCNU) are part of the standard repertoire in the therapy of malignant gliomas (CNS WHO grade 3 and 4). This review describes the ... ...

Abstract	The genotoxic methylating agents temozolomide (TMZ) and procarbazine and the chloroethylating nitrosourea lomustine (CCNU) are part of the standard repertoire in the therapy of malignant gliomas (CNS WHO grade 3 and 4). This review describes the mechanisms of their cytotoxicity and cytostatic activity through apoptosis, necroptosis, drug-induced senescence, and autophagy, interaction of critical damage with radiation-induced lesions, mechanisms of glioblastoma resistance to alkylating agents, including the alkyltransferase MGMT, mismatch repair, DNA double-strand break repair and DNA damage responses, as well as IDH-1 and PARP-1. Cyclin-dependent kinase inhibitors such as regorafenib, synthetic lethality using PARP inhibitors, and alternative therapies including tumor-treating fields (TTF) and CUSP9v3 are discussed in the context of alkylating drug therapy and overcoming glioblastoma chemoresistance. Recent studies have revealed that senescence is the main trait induced by TMZ in glioblastoma cells, exhibiting hereupon the senescence-associated secretory phenotype (SASP). Strategies to eradicate therapy-induced senescence by means of senolytics as well as attenuating SASP by senomorphics are receiving increasing attention, with therapeutic implications to be discussed.
Language	English
Publishing date	2023-11-30
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2662592-1
ISSN	2077-0383
ISSN	2077-0383
DOI	10.3390/jcm12237442
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Article ; Online: Temozolomide, Procarbazine and Nitrosoureas in the Therapy of Malignant Gliomas

Bernd Kaina

Journal of Clinical Medicine, Vol 12, Iss 23, p

Update of Mechanisms, Drug Resistance and Therapeutic Implications

2023 Volume 7442

Abstract	The genotoxic methylating agents temozolomide (TMZ) and procarbazine and the chloroethylating nitrosourea lomustine (CCNU) are part of the standard repertoire in the therapy of malignant gliomas (CNS WHO grade 3 and 4). This review describes the mechanisms of their cytotoxicity and cytostatic activity through apoptosis, necroptosis, drug-induced senescence, and autophagy, interaction of critical damage with radiation-induced lesions, mechanisms of glioblastoma resistance to alkylating agents, including the alkyltransferase MGMT, mismatch repair, DNA double-strand break repair and DNA damage responses, as well as IDH-1 and PARP-1. Cyclin-dependent kinase inhibitors such as regorafenib, synthetic lethality using PARP inhibitors, and alternative therapies including tumor-treating fields (TTF) and CUSP9v3 are discussed in the context of alkylating drug therapy and overcoming glioblastoma chemoresistance. Recent studies have revealed that senescence is the main trait induced by TMZ in glioblastoma cells, exhibiting hereupon the senescence-associated secretory phenotype (SASP). Strategies to eradicate therapy-induced senescence by means of senolytics as well as attenuating SASP by senomorphics are receiving increasing attention, with therapeutic implications to be discussed.
Keywords	glioblastoma ; temozolomide ; procarbazine ; CCNU ; therapy ; drug resistance ; Medicine ; R
Subject code	610
Language	English
Publishing date	2023-11-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: On the Origin of SARS-CoV-2: Did Cell Culture Experiments Lead to Increased Virulence of the Progenitor Virus for Humans?

Kaina, Bernd

In vivo (Athens, Greece)

2021 Volume 35, Issue 3, Page(s) 1313–1326

Abstract: We are currently in a rapidly expanding pandemic of the SARS-CoV-2 virus, which originated in the city of Wuhan in central China. The disease COVID-19 is now spread worldwide and has tremendous socio-economic consequences. The origin of the virus can be ... ...

Abstract	We are currently in a rapidly expanding pandemic of the SARS-CoV-2 virus, which originated in the city of Wuhan in central China. The disease COVID-19 is now spread worldwide and has tremendous socio-economic consequences. The origin of the virus can be reconstructed through epidemiological studies and, even more so, from genome comparisons. How the evolution of the virus and the transition to humans might have happened is the subject of much speculation. It is considered certain that the virus is of animal origin and very likely passed from bats to humans in a zoonotic event. An intermediate host was postulated, but many SARS-like bat viruses have the ability to infect human cells directly, which has been shown experimentally by scientists in the Wuhan Institute of Virology using collected specimens containing virus material from horseshoe bats. The propagation of SARS-like bat viruses in cell culture allowed experiments aimed at increasing the infectivity of the virus and adaptation to human cells. This article summarizes the unique properties of SARS-CoV-2 and focusses on a specific sequence encoding the spike protein. Possible scenarios of virus evolution are discussed, with particular emphasis on the hypothesis that the virus could have emerged unintentionally through routine culture or gain-of-function experiments in a laboratory, where it was optimally adapted to human cells and caused cryptic infections among workers who finally spread the virus causing the pandemic.
MeSH term(s)	Animals ; COVID-19 ; Cell Culture Techniques ; China/epidemiology ; Humans ; SARS-CoV-2 ; Virulence ; Viruses
Language	English
Publishing date	2021-04-28
Publishing country	Greece
Document type	Journal Article ; Review
ZDB-ID	807031-3
ISSN	1791-7549 ; 0258-851X
ISSN (online)	1791-7549
ISSN	0258-851X
DOI	10.21873/invivo.12384
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Article ; Online: A genome-wide screening for DNA repair genes: much more players than hitherto known.

Kaina, Bernd

Signal transduction and targeted therapy

2020 Volume 5, Issue 1, Page(s) 204

MeSH term(s)	Animals ; DNA Repair/genetics ; Genome-Wide Association Study ; Humans
Language	English
Publishing date	2020-09-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2886872-9
ISSN	2059-3635 ; 2095-9907
ISSN (online)	2059-3635
ISSN	2095-9907
DOI	10.1038/s41392-020-00314-4
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Article: Temozolomide in Glioblastoma Therapy: Role of Apoptosis, Senescence and Autophagy. Comment on Strobel et al., Temozolomide and Other Alkylating Agents in Glioblastoma Therapy.

Kaina, Bernd

Biomedicines

2019 Volume 7, Issue 4

Abstract: Temozolomide, a DNA methylating drug, is currently being used first-line in glioblastoma therapy. Although the mode of action of this so-called ... ...

Abstract	Temozolomide, a DNA methylating drug, is currently being used first-line in glioblastoma therapy. Although the mode of action of this so-called S
Language	English
Publishing date	2019-11-11
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2720867-9
ISSN	2227-9059
ISSN	2227-9059
DOI	10.3390/biomedicines7040090
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Article ; Online: Genotoxic and Cytotoxic Activity of Fisetin on Glioblastoma Cells.

Beltzig, Lea / Christmann, Markus / Dobreanu, Minodora / Kaina, Bernd

Anticancer research

2024 Volume 44, Issue 3, Page(s) 901–910

Abstract: Background/aim: Fisetin is a yellow-coloring flavonoid that can be found in a wide variety of plants, vegetables, and fruits, such as strawberries, apples, and grapes. It has been shown to have biological activity by targeting different pathways ... ...

Abstract	Background/aim: Fisetin is a yellow-coloring flavonoid that can be found in a wide variety of plants, vegetables, and fruits, such as strawberries, apples, and grapes. It has been shown to have biological activity by targeting different pathways regulating survival and death and to bear antioxidant and anti-inflammatory activity. Fisetin was shown to be cytotoxic on different cancer cell lines and has the ability to kill therapy-induced senescent cancer cells. The aim of the study was to investigate the DNA damaging and cytotoxic potential of fisetin and its ability to enhance the killing effect of temozolomide on glioblastoma cells. Materials and methods: We used LN229 glioblastoma cells and measured survival and apoptosis by flow cytometry, DNA strand breaks by the alkaline comet and γH2AX assay, and the DNA damage response by western blot analysis. Results: Fisetin was cytotoxic on glioblastoma cells, inducing apoptosis. In the dose range of 40-80 μM it also induced DNA damage, as measured by the alkaline comet and γH2AX assay, and triggered DNA damage response, as revealed by p53 activation. Furthermore, fisetin enhanced the genotoxic effect of methyl methanesulfonate, presumably due to inhibition of DNA repair processes. When administered together with temozolomide, the first-line therapeutic for glioblastoma, it enhanced cell death, reduced the yield of senescent cells following treatment and exhibited senolytic activity on glioblastoma cells. Conclusion: Data show that high-dose fisetin has a genotoxic potential and suggest that, harnessing the cytotoxic and senolytic activity of the flavonoid, it may enhance the effect of anticancer drugs and eliminate therapy-induced senescent cells. Therefore, it may be useful for adjuvant cancer therapy, including glioblastoma, which is worth to be studied in clinical trials.
MeSH term(s)	Humans ; Temozolomide/pharmacology ; Temozolomide/therapeutic use ; Glioblastoma/drug therapy ; Glioblastoma/metabolism ; Senotherapeutics ; Flavonols/pharmacology ; Flavonols/therapeutic use ; Antineoplastic Agents/pharmacology ; Flavonoids/pharmacology ; Apoptosis ; DNA Damage ; Cell Line, Tumor ; DNA
Chemical Substances	fisetin (OO2ABO9578) ; Temozolomide (YF1K15M17Y) ; Senotherapeutics ; Flavonols ; Antineoplastic Agents ; Flavonoids ; DNA (9007-49-2)
Language	English
Publishing date	2024-02-29
Publishing country	Greece
Document type	Journal Article
ZDB-ID	604549-2
ISSN	1791-7530 ; 0250-7005
ISSN (online)	1791-7530
ISSN	0250-7005
DOI	10.21873/anticanres.16884
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Article ; Online: Temozolomide in Glioblastoma Therapy

Bernd Kaina

Biomedicines, Vol 7, Iss 4, p

Role of Apoptosis, Senescence and Autophagy. Comment on Strobel et al., Temozolomide and Other Alkylating Agents in Glioblastoma Therapy. Biomedicines 2019, 7 , 69

2019 Volume 90

Abstract: Temozolomide, a DNA methylating drug, is currently being used first-line in glioblastoma therapy. Although the mode of action of this so-called S N 1 alkylating agent is well described, including the types of induced DNA damage triggering the DNA damage ... ...

Abstract	Temozolomide, a DNA methylating drug, is currently being used first-line in glioblastoma therapy. Although the mode of action of this so-called S N 1 alkylating agent is well described, including the types of induced DNA damage triggering the DNA damage response and survival and death pathways, some researchers expressed doubt that data mostly obtained by in vitro models can be translated into the in vivo situation. In experimental settings, high doses of the agent are often used, which are likely to activate responses triggered by base N-alkylations instead of O 6 -methylguanine ( O 6 MeG), which is the primary cytotoxic lesion induced by low doses of temozolomide and other methylating drugs in O 6 -methylguanine-DNA methyltransferase (MGMT) repair incompetent cells. However, numerous studies provided compelling evidence that O 6 MeG is not only a mutagenic, but also a powerful toxic lesion inducing DNA double-strand breaks, apoptosis, autophagy and cellular senescence. MGMT, repairing the lesion through methyl group transfer, is a key node in protecting cells against all these effects and has a significant impact on patient’s survival following temozolomide therapy, supporting the notion that findings obtained on a molecular and cellular level can be translated to the therapeutic setting in vivo. This comment summarizes the current knowledge on O 6 MeG-triggered pathways, including dose dependence and the question of thresholds, and comes up with the conclusion that data obtained on cell lines using low dose protocols are relevant and apoptosis, autophagy and senescence are therapeutically important endpoints.
Keywords	temozolomide ; alkylating agents ; dna repair ; apoptosis ; senescence ; Biology (General) ; QH301-705.5
Subject code	333
Language	English
Publishing date	2019-11-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: Artesunate in glioblastoma therapy: Case reports and review of clinical studies.

Strik, Herwig / Efferth, Thomas / Kaina, Bernd

Phytomedicine : international journal of phytotherapy and phytopharmacology

2023 Volume 123, Page(s) 155274

Abstract: Background: Artesunate, a derivative of the active ingredient artemisinin from Artemisia annua L. used for centuries in the traditional Chinese medicine, is being applied as front-line drug in malaria treatment. As it is cytotoxic for cancer cells, ... ...

Abstract	Background: Artesunate, a derivative of the active ingredient artemisinin from Artemisia annua L. used for centuries in the traditional Chinese medicine, is being applied as front-line drug in malaria treatment. As it is cytotoxic for cancer cells, trials are ongoing to include this drug as supplement in cancer therapy. In glioblastoma cells, artesunate was shown to induce oxidative stress, DNA base damage and double-strand breaks (DSBs), apoptosis, and necroptosis. It also inhibits DNA repair functions and bears senolytic activity. Compared to ionizing radiation, DNA damages accumulate over the whole exposure period, which makes the agent unique in its genotoxic profile. Artesunate has been used in adjuvant therapy of various cancers. Purpose: As artesunate has been used in adjuvant therapy of different types of cancer and clinical trials are lacking in brain cancer, we investigated its activity in glioma patients with focus on possible side effects. Study design: Between 2014 and 2020, twelve patients were treated with artesunate for relapsing glioma and analyzed retrospectively: 8 males and 4 females, median age 45 years. Histology: 4 glioblastomas WHO grade 4, 5 astrocytomas WHO grade 3, 3 oligodendrogliomas grade 2 or 3. All patients were pretreated with radiation and temozolomide-based chemotherapy. Artesunate 100 mg was applied twice daily p.o. combined with dose-dense temozolomide alone (100 mg/m Results: Apart from one transient grade 3 hematological toxicity, artesunate was well tolerated. No liver toxicity was observed. While 8 patients with late stage of the disease had a median survival of 5 months after initiation of artesunate treatment, 4 patients with treatment for remission maintenance showed a median survival of 46 months. We also review clinical trials that have been performed in other cancers where artesunate was included in the treatment regimen. Conclusions: Artesunate administered at a dose of 2 × 100 mg/day was without harmful side effects, even if combined with alkylating agents used in glioma therapy. Thus, the phytochemical, which is also utilized as food supplement, is an interesting, well tolerated supportive agent useful for long-term maintenance treatment. Being itself cytotoxic on glioblastoma cells and enhancing the cytotoxicity of temozolomide as well as in view of its senolytic activity, artesunate has clearly a potential to enhance the efficacy of malignant brain cancer therapy.
MeSH term(s)	Male ; Female ; Humans ; Middle Aged ; Glioblastoma/drug therapy ; Temozolomide/pharmacology ; Artesunate/pharmacology ; Artesunate/therapeutic use ; Dacarbazine ; Retrospective Studies ; Senotherapeutics ; Neoplasm Recurrence, Local ; Antineoplastic Agents/therapeutic use ; Brain Neoplasms/drug therapy ; Brain Neoplasms/pathology ; DNA/therapeutic use
Chemical Substances	Temozolomide (YF1K15M17Y) ; Artesunate (60W3249T9M) ; Dacarbazine (7GR28W0FJI) ; Senotherapeutics ; Antineoplastic Agents ; DNA (9007-49-2)
Language	English
Publishing date	2023-12-12
Publishing country	Germany
Document type	Case Reports ; Journal Article
ZDB-ID	1205240-1
ISSN	1618-095X ; 0944-7113
ISSN (online)	1618-095X
ISSN	0944-7113
DOI	10.1016/j.phymed.2023.155274
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Zs.A 4115: Show issues

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Article: Temozolomide - Just a Radiosensitizer?

Kaina, Bernd / Beltzig, Lea / Strik, Herwig

Frontiers in oncology

2022 Volume 12, Page(s) 912821

Abstract: Radiation concomitant with the DNA methylating drug temozolomide (TMZ) is the gold standard in the treatment of glioblastoma. In this adjuvant setting, TMZ is regarded to be a radiation sensitizer. However, similar to ionising radiation, TMZ induces DNA ... ...

Abstract	Radiation concomitant with the DNA methylating drug temozolomide (TMZ) is the gold standard in the treatment of glioblastoma. In this adjuvant setting, TMZ is regarded to be a radiation sensitizer. However, similar to ionising radiation, TMZ induces DNA double-strand breaks and is itself a potent trigger of apoptosis, cellular senescence and autophagy, suggesting that radiation and TMZ act independently. Although cell culture experiments yielded heterogeneous results, some data indicate that the cytotoxic effect of radiation was only enhanced when TMZ was given before radiation treatment. Based on the molecular mechanism of action of TMZ, the importance of specific TMZ and radiation-induced DNA lesions, their repair as well as their interactions, possible scenarios for an additive or synergistic effect of TMZ and radiation are discussed, and suggestions for an optimal timing of radio-chemical treatments are proposed.
Language	English
Publishing date	2022-06-16
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2022.912821
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Article ; Online: Abrogation of Cellular Senescence Induced by Temozolomide in Glioblastoma Cells: Search for Senolytics.

Beltzig, Lea / Christmann, Markus / Kaina, Bernd

Cells

2022 Volume 11, Issue 16

Abstract: A first-line therapeutic for high-grade glioma, notably glioblastoma (GBM), is the DNA methylating drug temozolomide (TMZ). Previously, we showed that TMZ induces not only apoptosis and autophagy, but also cellular senescence (CSEN). We presented the ... ...

Abstract	A first-line therapeutic for high-grade glioma, notably glioblastoma (GBM), is the DNA methylating drug temozolomide (TMZ). Previously, we showed that TMZ induces not only apoptosis and autophagy, but also cellular senescence (CSEN). We presented the hypothesis that GBM cells may escape from CSEN, giving rise to recurrent tumors. Furthermore, the inflammatory phenotype associated with CSEN may attenuate chemotherapy and drive tumor progression. Therefore, treatments that specifically target senescent cells, i.e., senolytic drugs, may lead to a better outcome of GBM therapy by preventing recurrences and tumor inflammation. Here, we tested Bcl-2 targeting drugs including ABT-737, ABT-263 (navitoclax), several natural substances such as artesunate, fisetin and curcumin as well as lomustine (CCNU) and ionizing radiation (IR) for their senolytic capacity in GBM cells. Additionally, several proteins involved in the DNA damage response (DDR), ATM, ATR, Chk1/2, p53, p21, NF-kB, Rad51, PARP, IAPs and autophagy, a pathway involved in CSEN induction, were tested for their impact in maintaining CSEN. Treatment of GBM cells with a low dose of TMZ for 8-10 days resulted in >80% CSEN, confirming CSEN to be the major trait induced by TMZ. To identify senolytics, we treated the senescent population with the compounds of interest and found that ABT-737, navitoclax, chloroquine, ATMi, ATRi, BV-6, PX-866 and the natural compounds fisetin and artesunate exhibit senolytic activity, inducing death in senescent cells more efficiently than in proliferating cells. Curcumin showed the opposite effect. No specific effect on CSEN cells was observed by inhibition of Chk1/Chk2, p21, NF-kB, Rad51 and PARP. We conclude that these factors neither play a critical role in maintaining TMZ-induced CSEN nor can their inhibitors be considered as senolytics. Since IR and CCNU did not exhibit senolytic activity, radio- and chemotherapy with alkylating drugs is not designed to eliminate TMZ-induced senescent cancer cells.
MeSH term(s)	Artesunate/pharmacology ; Cellular Senescence ; Curcumin/pharmacology ; Glioblastoma/metabolism ; Humans ; Lomustine/pharmacology ; Lomustine/therapeutic use ; NF-kappa B ; Neoplasm Recurrence, Local/drug therapy ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Senotherapeutics ; Temozolomide/pharmacology ; Temozolomide/therapeutic use
Chemical Substances	NF-kappa B ; Poly(ADP-ribose) Polymerase Inhibitors ; Senotherapeutics ; Artesunate (60W3249T9M) ; Lomustine (7BRF0Z81KG) ; Curcumin (IT942ZTH98) ; Temozolomide (YF1K15M17Y)
Language	English
Publishing date	2022-08-19
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells11162588
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